US5134134A - Unsaturated aminodicarboxylic acid derivatives - Google Patents

Unsaturated aminodicarboxylic acid derivatives Download PDF

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US5134134A
US5134134A US07/699,412 US69941291A US5134134A US 5134134 A US5134134 A US 5134134A US 69941291 A US69941291 A US 69941291A US 5134134 A US5134134 A US 5134134A
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alkoxycarbonyl
compound
formula
salt
phenyl
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Hans Allgeier
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Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/44—Amides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3826—Acyclic unsaturated acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to unsaturated aminodicarboxylic derivatives of formula I ##STR3## wherein A is a divalent aliphatic hydrocarbon radical containing 2 carbon atoms and R 1 and R 2 are each independently of the other free or esterified carboxyl groups, and to salts thereof, to the preparation of said compounds, to pharmaceutical compositions containing them, and to the use thereof as medicinal agents.
  • Divalent aliphatic hydrocarbon radicals containing 2 carbon atoms are, typically, 1,2-ethylene or 1,2-vinylene.
  • Esterfied carboxy is, typically, carboxy esterified with an aliphatic or araliphatic alcohol and is lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl which is unsubstituted or substituted, for example, by lower alkyl, lower alkoxy, halogen, cyano and/or trifluoromethyl, and the phenyl moiety of phenyl-lower alkoxycarbonyl R 2 may carry one or more, for example two or three, of the cited substituents.
  • Lower alkyl may be C 1 -C 7 alkyl, preferably C 1 -C 4 alkyl such as preferably methyl or, less preferably, ethyl, propyl, isopropyl or butyl, but may also be isobutyl, sec.-butyl, tert.-butyl or C 1 -C 5 alkyl such as pentyl, hexyl or heptyl.
  • Lower alkoxy may be C 1 -C 7 alkoxy, preferably C 1 -C 4 alkoxy such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but may also be isobutyloxy, sec.-butyloxy, tert.-butyloxy or pentyloxy, hexyloxy or heptyloxy.
  • Lower alkoxycarbonyl may be C 1 -C 7 alkoxycarbonyl, preferably C 1 -C 4 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl, but may also be a C 5 -C 7 -alkoxyisopropoxycarbonyl or butoxycarbonyl group, and also a C 5 -C 7 -alkoxycarbonyl group such as pentyloxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl group.
  • Phenyl-lower alkoxycarbonyl may be phenyl-C 1 -C 4 alkoxycarbonyl such as benzyloxycarbonyl, 2-phenylethoxycarbonyl or, less preferably, 3-phenylpropoxycarbonyl or 4-phenylbutoxycarbonyl.
  • Halogen is typically, halogen having an atomic number of up to 35 inclusive, such as chloro or fluoro and also bromo.
  • the compounds of formula I are obtained in the form of their inner salts and can form acid addition salts as well as salts with bases.
  • acid addition salts of compounds of formula I are the pharmaceutically acceptable salts thereof with suitable mineral acids such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates, benzen
  • Salts of compounds of formula I are in particular the salts thereof with pharmaceutically acceptable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, IIa and IIb, e.g. alkali metal salts, preferably sodium or potassium salts, alkaline earth metal salts, preferably calcium or magnesium salts, copper, aluminium or zinc salts, and also ammonium salts with ammonia or organic amines or quaternary ammonium bases such as free or C-hydroxylated aliphatic amines, preferably mono-, di-or tri-lower alkylamines, e.g.
  • bases such as non-toxic metal salts derived from metals of groups Ia, Ib, IIa and IIb, e.g. alkali metal salts, preferably sodium or potassium salts, alkaline earth metal salts, preferably calcium or magnesium salts, copper, aluminium or zinc salts, and also ammonium salts with ammonia or organic amines or quaternary am
  • methylamine, ethylamine, dimethylamine or diethylamine, mono-, di- or tri(hydroxylower alkyl)amines such as ethanolamine, diethanolamine or triethanolamine, tris-(hydroxymethyl)aminomethane or 2-hydroxy-tert.-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-lower alkylamines or N-(polyhydroxy-lower alkyl)-N-lower alkylamines such as 2-(dimethylamino)ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, e.g. with tetrabutylammonium hydroxide.
  • the compounds of formula I have valuable pharmacological properties.
  • they have a marked and selective antagonistic action against N-methyl-D-aspartic acid sensitive (NMDA-sensitive) excitatory amino acid receptors of warm-blooded animals.
  • NMDA-sensitive N-methyl-D-aspartic acid sensitive excitatory amino acid receptors of warm-blooded animals.
  • This can be determined in vitro, for example in the experimental procedure of G. Fagg and A. Matus, Proc. Nat. Acad. Sci., USA, 81, 6876-80 (1984). In this procedure, it is determined to what extent the binding of L- 3 H-glutamic acid to NMDA receptors is inhibited.
  • the NMDA antagonistic properties can, however, also be demonstrated in vivo, for example in mice, by means of the inhibitory action on NMDA-induced convulsions.
  • the anticonvulsive properties of the compounds of this invention can be determined, for example, in mice by means of their marked protective action against convulsions induced by electroshock or audiogenically induced convulsions, for which purpose, for example, the established electroshock mouse model or the experimental procedure of Chapman et al., Arzneistoff-Forsch. 34, 1261 (1984) may be used.
  • the compounds of this invention are distinguished in these procedures, especially in the electroshock mouse model, by improved activity as compared with structurally related compounds.
  • the compounds of formula I and the pharmaceutically acceptable salts thereof are most suitable for the treatment of pathological states which respond to a blocking of NMDA-sensitive receptors, for example of cerebral ischaemia, ischaemic diseases of the eye, muscle spasms such as local or general spasticity and, in particular, of convulsions.
  • the invention relates in particular to compounds of formula I, wherein A is lower alkylene or lower alkenylene containing 2 carbon atoms, and R 1 and R 2 are each independently of the other carboxy, lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, cyano and/or trifluoromethyl and the salts thereof.
  • the invention relates to compounds of formula I, wherein A is 1,2-ethylene or 1,2-vinylene, R 1 is carboxy, C 1 -C 4 alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, or phenyl-C 1 -C 4 alkoxycarbonyl which is unsubstituted or substituted by C 1 -C 4 alkyl such as methyl, C 1 -C 4 alkoxy such as methoxy, halogen having an atomic number of up to 35 inclusive, such as fluoro or chloro, cyano and/or trifluoromethyl, for example benzyl- or 2-phenylethoxycarbonyl, and R 2 is carboxy, C 1 -C 4 alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, or phenyl-C 1 -C 4 -alkoxycarbonyl which is unsubstituted or substituted by C 1 -C 4 alkyl such as methyl
  • the invention relates to compounds of formula I, wherein A is 1,2-ethylene, and R 1 and R 2 are identical or different C 1 -C 4 alkoxycarbonyl or phenyl-C 1 -C 4 -alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl, and their salts, especially their pharmaceutically acceptable, salts.
  • the invention relates to the compounds of formula I and their salts, preferably pharmaceutically acceptable salts, named in the Examples.
  • the process for the preparation of the compounds of this invention comprises converting, in a compound of formula II ##STR4## wherein Z 1 and Z 2 are hydroxy or protected hydroxy and Z 3 is protected amino, Z 3 into amino and, if present, converting protected hydroxyl groups Z 1 and/or Z 2 into hydroxy and, if desired, converting a resultant compound into another compound of formula I, resolving a resultant mixture of isomers into the individual components and separating the desired preferred isomer and/or converting a resultant free compound into a salt or a resultant salt into the corresponding free compound.
  • protected hydroxy Z 1 and/or Z 2 may be etherified hydroxy, preferably aliphatic etherified hydroxy, for example lower alkoxy such as methoxy, ethoxy or, preferably, isopropyloxy, and protected amino Z 3 may be acylated or silylated amino.
  • the acyl group in acylated amino may be derived from an organic acid such as an aliphatic or aromatic mono- or dicarboxylic acid or from an aliphatic, araliphatic or aromatic half-ester of carbonic acid.
  • Acylated amino may therefore be lower alkanoylamino such as formylamino, acetylamino or pivaloylamino, benzoylamino which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and/or nitro, lower alkoxycarbamoyl such as methoxy-, ethoxy or tert.-butoxycarbamoyl, phenyl-lower alkoxycarbamoyl which may be substituted in the phenyl moiety by lower alkyl, lower alkoxy, halogen and/or nitro, for example benzyloxycarbamoyl, or phenoxycarbamoyl which is substituted by
  • Silylated amino may be tri-lower alkylsilylamino such as trimethylsilylamino or tributylsilylamino.
  • the liberation of the protected groups from compounds of formula II may be effected by treatment with an acid agent, for example a tri-lower alkylhalosilane such as trimethylbromosilane, tributylbromosilane or trimethyliodosilane or, in particular for the preparation of compounds of formula I, wherein R 1 and R 2 are carboxy, with an aqueous mineral acid such as strong, for example 6-normal, hydrochloric acid.
  • an acid agent for example a tri-lower alkylhalosilane such as trimethylbromosilane, tributylbromosilane or trimethyliodosilane or, in particular for the preparation of compounds of formula I, wherein R 1 and R 2 are carboxy, with an aqueous mineral acid such as strong, for example 6-normal, hydrochloric acid.
  • an inert solvent such as a halogenated aliphatic hydrocarbon, for example dichloromethane or, less preferably, tri- or tetrachloromethane, trichloroethane or tetrachloroethane, for example in the temperature range from approximately -25° to approximately +50° C., preferably from approximately 0° to 30° C., for example at room temperature, i.e. in the range from approximately 15° to 25° C., conveniently under essentially anhydrous conditions and in an inert gas atmosphere such as argon or nitrogen.
  • a halogenated aliphatic hydrocarbon for example dichloromethane or, less preferably, tri- or tetrachloromethane, trichloroethane or tetrachloroethane
  • Working up is conveniently effected by adding a hydrohalic acid acceptor, preferably an aliphatic epoxy compound such as an epoxy-lower alkane, for example propylene oxide in a lower alkanol such as ethanol.
  • a hydrohalic acid acceptor preferably an aliphatic epoxy compound such as an epoxy-lower alkane, for example propylene oxide in a lower alkanol such as ethanol.
  • the treatment with an aqueous mineral acid is carried out preferably with heating, for example to a temperature in the range from approximately 60° to 120° C., preferably to boiling temperature.
  • a preferred embodiment of the process of the invention comprises starting from compounds of formula II, wherein Z 1 and Z 2 are lower alkoxy such as isopropyloxy, and Z 3 is lower alkanoylamino such as formylamino, or lower alkoxycarbamoyl such as tert.-butoxycarbamoyl, and treating said compounds in an aliphatic hydrocarbon such as dichloromethane, in the temperature range from approximately 15° to approximately 25° C., with a tri-lower alkylbromosilane such as trimethylbromosilane or tributylbromosilane, allowing the reaction mixture to react for some time, for example approximately 2 to 30 hours, then adding an ethanolic solution of propylene oxide, and isolating the product by filtration.
  • Z 1 and Z 2 are lower alkoxy such as isopropyloxy
  • Z 3 is lower alkanoylamino such as formylamino, or lower alkoxycarbamoyl such as tert.
  • Starting materials of formula II may be prepared by reacting an ⁇ , ⁇ -unsaturated aldehyde of formula IIa ##STR5## with an ⁇ -isocyanoacetate of formula IIb ##STR6## in a manner known per se, for example in the presence of a copper or gold catalyst, for example of copper(I) oxide or, preferably, of bis(cyclohexylisocyanide) gold(I) tetrafluoroborate, in the presence of a compound of formula X ##STR7## wherein one of the substituents L 1 and L 2 and PPh 2 is diphenylphosphino and the other is hydrogen, and one of the substituents R 1 and R 2 is methyl and the other is hydrogen, to the corresponding 5-substituted 2-oxazoline-4-carboxylate of formula IIc ##STR8## converting said compound of formula IIc by hydrolysis, for example in aqueous tetrahydrofuran, into the corresponding open-chain ester of
  • free and esterified carboxyl groups R 1 and R 2 can be converted in conventional manner into each other.
  • esterified carboxy can be transesterified to another esterified carboxy group.
  • an acid for example a mineral acid such as hydrochloric acid or sulfuric acid
  • a base such as an alkali metal hydroxide, for example sodium hydroxide.
  • an acid for example a mineral acid such as hydrochloric acid or sulfuric acid, if necessary in the presence of 4-(N,N-dimethylamino)-pyradine and/or of a condensing agent such as N,N-dicyclohexylcarbodiimide.
  • a catalytic amount of a mineral acid such as hydrochloric acid or sulfuric acid
  • a metal alcoholate for example an alkali metal alcoholate.
  • Salts can be converted in a manner known per se into the free compounds, for example by treatment with a abase such as an alkali metal hydroxide, a metal carbonate or metal hydrogencarbonate, or ammonia, or with another salt-forming base initially mentioned or with an acid, for example a mineral acid such as hydrochloric acid, or with another salt-forming acid initially mentioned.
  • a abase such as an alkali metal hydroxide, a metal carbonate or metal hydrogencarbonate, or ammonia
  • an acid for example a mineral acid such as hydrochloric acid, or with another salt-forming acid initially mentioned.
  • Salts can be converted in a manner known per se into other salts.
  • acid addition salts can be converted into other salts by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of another acid in a suitable solvent in which an inorganic salt that forms is insoluble and therefore precipitates from the reaction mixture, and basic salts by liberating the free acid and renewed salt-formation.
  • a suitable metal salt such as a sodium, barium or silver salt
  • the compounds of formula I can be also be obtained in the form of hydrates or may contain the solvent used for crystallization in their crystal structure.
  • Resultant mixtures of diastereomers and mixtures of racemates can be separated in known manner into the pure diastereomers or racemates on the basis of the physico-chemical differences between the components, for example by chromatography and/or fractional crystallization.
  • Resultant racemates can also be resolved into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by reacting the mixture of diastereomers or racemate with an optically active compound, for example in accordance with the acid, basic or functionally modified groups present in compounds of formula I, with an optically active acid, base or an optically active alcohol, to form mixtures of diastereomers salts or functional derivatives such as esters, and separating the latter into the diastereomers from which the desired enantiomers can be isolated in the appropriate conventional manner.
  • bases, acids and alcohols suitable for this purpose are optically active alkaloid bases such as strychnine, cinchonine or brucine, or D-or L-(-1-phenyl)-ethylamine, 3-pipecoline, ephedrine, amphetamine and similar synthetically obtainable bases, optically active carboxylic or sulfonic acids such as quinic acid or D- or L-tartaric acid, di-o-toluyltartaric acid, malic acid, mandelic acid or camphorsulphonic acid, or optically active alcohols such as borneol or D- or L-(1-phenyl)ethanol.
  • optically active alkaloid bases such as strychnine, cinchonine or brucine, or D-or L-(-1-phenyl)-ethylamine, 3-pipecoline, ephedrine, amphetamine and similar synthetically obtainable bases
  • optically active carboxylic or sulfonic acids such as quinic acid
  • the invention also relates to those embodiments of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out, or a starting material is used in the form of a salt or, preferably, is formed under the reaction conditions.
  • the invention also relates to novel starting materials developed specifically for the preparation of the compounds of the invention, especially the group of starting materials that result in the compounds of formula I referred to at the outset as being preferred, to processes for their preparation, and to their use as intermediates.
  • novel compounds of formula I may be used for example in the form of pharmaceutical compositions that contain a therapeutically effective amount of active ingredient, optionally together with inorganic or organic, solid or liquid pharmaceutically acceptable carriers that are suitable for enteral, e.g. oral, or parenteral administration.
  • the compositions employed are tablets or gelatin capsules which contain the active ingredient together with diluents, e.g. lactose, dextrose, saccharose, mannitol, sorbitol, cellulose and/or lubricants, e.g. silica, talcum, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Tablets may also contain binders, e.g.
  • novel compounds of formula I may also be used in the form of compositions for parenteral administration or of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions which, e.g.
  • lyophilized formulations that contain the active ingredient alone or together with a carrier, e.g. mannitol, may be prepared prior to use.
  • the pharmaceutical compositions may be sterilized and/or may contain adjuvants, e.g. preservatives, stabilizers, wetting agents and/or emulsifiers, sublicenses, salts for regulating the osmotic pressure and/or buffers.
  • the pharmaceutical compositions of the invention may, if desired, contain further pharmacologically active substances, are prepared in a manner known per se, e.g. by conventional mixing, granulating, confectioning, dissolving or lyophilizing methods, and contain from about 0.1 to 100%, preferably from about 1 to 50% (lyophilizates up to 100%), of active ingredient.
  • the invention also relates to the use of compounds of formula I, preferably in the form of pharmaceutical compositions.
  • the dosage may depend on different factors, such as the mode of application, species, age and/or the individual condition of the patient.
  • the daily doses for oral administration are in the range from about 0.25 to 10 mg/kg, and for warm-blooded animals having a body weight of about 70 kg, preferably in daily doses of about 20 mg to 500 mg.
  • the starting material can be prepared as follows:
  • the batch is evaporated to dryness and the residue is chromatographed over slica gel with a 9:1 mixture of toluene/isopropanol as eluant, giving diethyl 2-formylamino-3-hydroxy-4-methylene-heptane-1,7-dicarboxylate as a brownish oil.
  • the crystalline precipitate formed is collected, re-crystallized twice from water and dried over phosphorus pentoxide, affording dibenzyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate of m.p. 220°-221° (decomp).
  • Tablets which each contain 50 mg of diethyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate or a salt, for example the sodium salt, thereof, can be prepared as follows:
  • composition for 1000 tablets
  • potato starch 352.0 g
  • magnesium stearate 10.0 g
  • the active ingredient is mixed with the lactose and 292 g of potato starch and this mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve.
  • the granulate is dried and then mixed with the remainder of the potato starch, the talcum, the magnesium stearate and the highly disperse silica and the mixture is compressed to tablets weighing 145.0 g each and containing 50.0 mg of active ingredient. If desired, the tablets may be provided with a breaking notch for a finer adjustment of the dose.
  • Film-coated tablets which each contain 100 mg of diethyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate or a salt, for example the sodium salt, thereof, can be prepared as follows:
  • composition for 1000 tablets
  • corn starch 70.00 g
  • hydroxypropylmethyl cellulose 2.36 g
  • the active ingredient, the lactose and 40 g of the corn starch are mixed and moistened with a paste prepared from 15 g of corn starch and water (with heating) and the mixture is granulated.
  • the granulate is dried and mixed with the remainder of the corn starch, talcum and the calcium stearate.
  • the mixture is compressed to tablets weighing 280 g.
  • the tablets are then coated with a solution of the hydroxypropylmethyl cellulose and the shellac in methylene chloride.
  • the coated tablets have a final weight of 283 g.
  • Hard gelatin capsules containing 100 mg of active ingredient for example diethyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate or a salt, for example the sodium salt, thereof, can be prepared as follows:
  • Composition for 1000 capsules
  • microcrystalline cellulose 30.0 g
  • magnesium stearate 8.0 g
  • the sodium lauryl sulfate is sieved through a sieve having a mesh size of 0.2 mm and added to the active ingredient (lyophilized) and both components are intimately mixed for 10 minutes.
  • the lactose is sieved through a sieve having a mesh size of 0.6 mm and then the microcrystalline cellulose is sieved through a sieve having a mesh size of 0.9 mm, added to the above mixture, and the ingredients are intimately mixed for 10 minutes.
  • the magnesium is sieved through a sieve having a mesh size of 0.8 mm, added to the mixture, and all the ingredients are mixed for 3 minutes. Size 0 hard gelatin capsules are filled with 390 mg of this mixture.
  • a 0.2% injection or infusion solution of diethyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7-dicarboxylate or a salt, for example the sodium salt, thereof, can be prepared as follows:
  • composition for 1000 ampoules
  • the active ingredient and the sodium chloride are dissolved in 1000 ml of water and filtered through a microfilter.
  • the buffer solution is added, followed by the addition of water to make up 2500 ml.

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Cited By (2)

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US5294734A (en) * 1989-09-26 1994-03-15 Ciba-Geigy Corp. 4-substituted 2-aminoalk-3-enoic acids
US5488140A (en) * 1989-09-26 1996-01-30 Ciba-Geigy Corporation 4-substituted 2-aminoalk-3-enoic

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5175344A (en) * 1986-02-13 1992-12-29 Ciba-Geigy Corporation Unsaturated amino acids
ATE112282T1 (de) * 1989-04-07 1994-10-15 Ciba Geigy Ag Ungesättigte aminodicarbonsäurederivate.
EP3427729A1 (de) 2017-07-13 2019-01-16 Paris Sciences et Lettres - Quartier Latin Probenecid zur behandlung von epileptischen erkrankungen, störungen oder zuständen

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NO176913B (no) 1995-03-13
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PT93675A (pt) 1990-11-20
HU207336B (en) 1993-03-29
EP0391850B1 (de) 1994-09-28
JPH02290889A (ja) 1990-11-30
FI94346C (fi) 1995-08-25
NZ233220A (en) 1992-08-26
HUT53658A (en) 1990-11-28
KR900016240A (ko) 1990-11-13
AU5293190A (en) 1990-10-11
EP0391850A3 (de) 1991-03-13
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DK0391850T3 (da) 1994-10-24
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CA2013919A1 (en) 1990-10-07
MX20200A (es) 1994-05-31
DE59007300D1 (de) 1994-11-03
AU639450B2 (en) 1993-07-29
IE901255L (en) 1990-10-07
FI94346B (fi) 1995-05-15
FI901709A0 (fi) 1990-04-04
DD298931A5 (de) 1992-03-19
IL93960A (en) 1994-08-26
NO901579L (no) 1990-10-08
HU902114D0 (en) 1990-07-28
NO176913C (no) 1995-06-21
ZA902636B (en) 1990-12-28
NO901579D0 (no) 1990-04-06
IE65571B1 (en) 1995-11-01

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